ES2586245T3 - Carboxamidas cuaternarias opioides - Google Patents
Carboxamidas cuaternarias opioides Download PDFInfo
- Publication number
- ES2586245T3 ES2586245T3 ES08797495.2T ES08797495T ES2586245T3 ES 2586245 T3 ES2586245 T3 ES 2586245T3 ES 08797495 T ES08797495 T ES 08797495T ES 2586245 T3 ES2586245 T3 ES 2586245T3
- Authority
- ES
- Spain
- Prior art keywords
- hydrogen
- compound
- alkyl
- morphine
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000003857 carboxamides Chemical group 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 abstract description 20
- 239000001257 hydrogen Substances 0.000 abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 6
- 150000002431 hydrogen Chemical group 0.000 abstract description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 125000006823 (C1-C6) acyl group Chemical group 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- -1 dimethylvinyl Chemical group 0.000 abstract 3
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 abstract 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 abstract 2
- JYNZIOFUHBJABQ-UHFFFAOYSA-N allyl-{6-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-hexyl-}-methyl-amin Chemical compound C=1OC2=CC(OCCCCCCN(C)CC=C)=CC=C2C=1C1=CC=C(Br)C=C1 JYNZIOFUHBJABQ-UHFFFAOYSA-N 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 abstract 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 abstract 1
- 125000002541 furyl group Chemical group 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 abstract 1
- 229920002554 vinyl polymer Chemical group 0.000 abstract 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 36
- 229960005181 morphine Drugs 0.000 description 20
- 230000004044 response Effects 0.000 description 19
- 238000012360 testing method Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- KPJPHPFMCOKUMW-UHFFFAOYSA-N iodomethane Chemical compound I[CH2] KPJPHPFMCOKUMW-UHFFFAOYSA-N 0.000 description 11
- 230000006870 function Effects 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000007912 intraperitoneal administration Methods 0.000 description 9
- 206010012735 Diarrhoea Diseases 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 230000036592 analgesia Effects 0.000 description 7
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 7
- 229960002986 dinoprostone Drugs 0.000 description 7
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 7
- QAICPHMNUHNDMC-WUHBCXKYSA-N (4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide Chemical compound C([C@@]12[C@@]3(O)CCC(=O)[C@@H]1OC=1C(C(N)=O)=CC=C(C2=1)C[C@]31[H])CN1CC1CC1 QAICPHMNUHNDMC-WUHBCXKYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 5
- MWKGWVXYJYQQQA-MBPVOVBZSA-N (4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carbonitrile Chemical compound C([C@@]12[C@@]3(O)CCC(=O)[C@@H]1OC=1C(C#N)=CC=C(C2=1)C[C@]31[H])CN1CC1CC1 MWKGWVXYJYQQQA-MBPVOVBZSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000003502 anti-nociceptive effect Effects 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229940126543 compound 14 Drugs 0.000 description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229960003086 naltrexone Drugs 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- RYIDHLJADOKWFM-MAODMQOUSA-N Samidorphan Chemical compound N1([C@@H]2CC3=CC=C(C(=C3[C@@]3([C@]2(CCC(=O)C3)O)CC1)O)C(=O)N)CC1CC1 RYIDHLJADOKWFM-MAODMQOUSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 4
- 239000003401 opiate antagonist Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 230000002093 peripheral effect Effects 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 101100219382 Caenorhabditis elegans cah-2 gene Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000020341 sensory perception of pain Effects 0.000 description 2
- 238000002096 two-dimensional nuclear Overhauser enhancement spectroscopy Methods 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940051805 benzomorphan derivative analgesics Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 1
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 1
- FAVQVALXVLMHLE-BKBNBNODSA-N dnc006841 Chemical compound C([C@]1(C)C2=CC(=CC=C2CC2[C@@H]1C)C(N)=O)CN2CC1CC1 FAVQVALXVLMHLE-BKBNBNODSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 230000008991 intestinal motility Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229940051807 opiod analgesics morphinan derivative Drugs 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000031070 response to heat Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/16—Peri-condensed systems
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- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- Chemical Kinetics & Catalysis (AREA)
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- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (3)
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| US95496007P | 2007-08-09 | 2007-08-09 | |
| US954960P | 2007-08-09 | ||
| PCT/US2008/072632 WO2009023567A1 (en) | 2007-08-09 | 2008-08-08 | Quaternary opioid carboxamides |
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| ES2586245T3 true ES2586245T3 (es) | 2016-10-13 |
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| CN103275004A (zh) * | 2007-11-30 | 2013-09-04 | 普渡制药公司 | 苯并吗啡烷化合物 |
| CA2754984C (en) * | 2009-03-19 | 2018-06-26 | Alkermes, Inc. | Morphinan derivatives with high oral bioavailability |
| WO2011068594A1 (en) | 2009-12-04 | 2011-06-09 | Alkermes, Inc. | Morphinan derivatives for the treatment of drug overdose |
| AU2011232628B2 (en) * | 2010-03-22 | 2015-04-09 | Rensselaer Polytechnic Institute | Morphinane derivatives containing a carboxamide group as opioid receptor ligands |
| JP5728084B2 (ja) * | 2010-07-08 | 2015-06-03 | アルカーメス ファーマ アイルランド リミテッド | 置換モルフィナンの合成のための方法 |
| EP2407469A1 (en) * | 2010-07-13 | 2012-01-18 | Chemo Ibérica, S.A. | Salt of sitagliptin |
| SI3446565T1 (sl) | 2010-08-23 | 2024-03-29 | Alkermes Pharma Ireland Limited | Metode zdravljenja povečanja teže, povzročene z antipsihotiki |
| JP2014505113A (ja) * | 2011-02-14 | 2014-02-27 | アルカーメス，インコーポレイテッド | 末梢作用性μオピオイドアンタゴニスト |
| CN104788456A (zh) * | 2011-03-03 | 2015-07-22 | 卡迪拉保健有限公司 | Dpp-iv抑制剂的新的盐 |
| WO2012138888A1 (en) * | 2011-04-05 | 2012-10-11 | Alkermes, Inc. | Process for the synthesis of quaternary amine compounds |
| SMT201700400T1 (it) * | 2011-06-29 | 2017-09-07 | Alkermes Inc | Composti oppioidi ad azione periferica |
| AU2012324012A1 (en) * | 2011-12-08 | 2013-06-27 | Purdue Pharma L.P. | Quaternized buprenorphine analogs |
| TR201815154T4 (tr) | 2011-12-15 | 2018-11-21 | Alkermes Pharma Ireland Ltd | Depresi̇f bozukluklarin tedavi̇si̇ne yöneli̇k buprenorfi̇n i̇le kombi̇nasyon hali̇nde sami̇dorfan (alks 33). |
| US9211293B2 (en) | 2011-12-15 | 2015-12-15 | Alkermes Pharma Ireland Limited | Opioid agonist antagonist combinations |
| US20140066475A1 (en) | 2012-09-04 | 2014-03-06 | Euro-Celtique S.A. | Method For Treating Pruritus |
| US9656961B2 (en) | 2013-05-24 | 2017-05-23 | Alkermes Pharma Ireland Limited | Methods for treating depressive symptoms |
| NZ631018A (en) | 2013-05-24 | 2017-12-22 | Alkermes Pharma Ireland Ltd | Morphan and morphinan analogues, and methods of use |
| WO2016138103A1 (en) * | 2015-02-25 | 2016-09-01 | Alkermes, Inc. | Treatments for alzheimer's related diseases and disorders |
| CN113248435B (zh) * | 2020-02-13 | 2024-06-04 | 上海翰森生物医药科技有限公司 | 3-甲酰胺基-4-羟基纳曲酮氘代衍生物、其制备方法及其在医药上的应用 |
| WO2022101444A1 (en) | 2020-11-12 | 2022-05-19 | Alkermes Pharma Ireland Limited | Immediate release multilayer tablet |
| CN115521317B (zh) * | 2021-02-02 | 2025-07-25 | 山东新时代药业有限公司 | 一种制备纳呋拉啡中间体的方法 |
| WO2025104754A1 (en) * | 2023-11-17 | 2025-05-22 | Msn Laboratories Private Limited, R&D Center | A process for the preparation of samidorphan and its intermediates |
| CN118598813B (zh) * | 2024-08-08 | 2024-10-29 | 山东齐都药业有限公司 | L-苹果酸萨米多芬及其制备方法 |
Family Cites Families (21)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB874217A (en) * | 1958-10-30 | 1961-08-02 | Albert Boehringer | Normorphine derivatives |
| DE2254298A1 (de) * | 1972-11-06 | 1974-05-16 | Boehringer Sohn Ingelheim | Neue (heteroarylmethyl)-normorphine, deren saeureadditionssalze, verfahren zu deren herstellung sowie deren verwendung als arzneimittel |
| US4032529A (en) | 1974-09-20 | 1977-06-28 | Sterling Drug Inc. | Aminomethanobenzazocine intermediates |
| GB1511319A (en) * | 1974-09-20 | 1978-05-17 | Sterling Drug Inc | 2,6-methane-3-benzazocine derivatives and their preparation |
| US4176186A (en) * | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
| FR2514644A1 (fr) | 1981-10-19 | 1983-04-22 | Sanofi Sa | Composition pharmaceutique a action antagoniste peripherique des opiaces |
| CA1315689C (en) * | 1987-09-03 | 1993-04-06 | Leon I. Goldberg | Quarternary derivatives of noroxymorphone which relieve nausea and emesis |
| AU706370B2 (en) * | 1996-01-10 | 1999-06-17 | Smithkline Beecham Spa | Heterocycle-condensed morphinoid derivatives (II) |
| ES2121553B1 (es) * | 1996-12-23 | 1999-06-16 | Univ Santiago Compostela | Nuevos endoperoxidos morfinicos funcionalizados en posiciones c-6 y c-14 del anillo c y procedimiento para su obtencion. |
| WO2001014382A1 (en) * | 1999-08-23 | 2001-03-01 | Toray Industries, Inc. | Analgesics containing as the active ingredient quaternary ammonium salt derivatives of morphinan |
| EP1206264A2 (en) * | 1999-08-25 | 2002-05-22 | Barrett R. Cooper | Compositions and methods for treating opiate intolerance |
| WO2001037785A2 (en) * | 1999-11-29 | 2001-05-31 | Adolor Corporation | Novel methods and compositions involving opioids and antagonists thereof |
| EP1359146B1 (en) * | 2000-10-31 | 2008-04-09 | Rensselaer Polytechnic Institute | 4-aryl piperidines as opioid receptor binding agents |
| US7375082B2 (en) * | 2002-02-22 | 2008-05-20 | Shire Llc | Abuse-resistant hydrocodone compounds |
| DE10229842A1 (de) | 2002-07-03 | 2004-02-05 | Helmut Prof. Dr. Schmidhammer | Morphinanderivate und deren quartäre Ammoniumsalze substituiert in Position 14, Herstellungsverfahren und Verwendung |
| EP1543010B1 (en) * | 2002-09-25 | 2007-04-25 | Euro-Celtique S.A. | N-substituted hydromorphones and the use thereof |
| PT1562953E (pt) * | 2002-11-08 | 2009-11-19 | Mallinckrodt Inc | Processo para a preparação de sais quaternários de n -alquilmorfinano |
| PL2251330T3 (pl) | 2004-11-05 | 2012-12-31 | Rensselaer Polytech Inst | 4-hydroksybenzomorfany |
| EP1861096B1 (en) | 2005-03-07 | 2018-12-26 | The University of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| EP2266959B1 (en) | 2005-07-21 | 2013-05-01 | Rensselaer Polytechnic Institute | 8-carboxamido-substituted-2, 6-methano-3-benzazocines and 3-carboxamido-substituted morphanes as opioid receptor binding agents |
| EP1928881A2 (en) * | 2005-08-19 | 2008-06-11 | Pharmacofore, Inc. | Prodrugs of active agents |
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| US20120302594A1 (en) | 2012-11-29 |
| EP2190819A1 (en) | 2010-06-02 |
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| NO341089B1 (no) | 2017-08-21 |
| MX2010001371A (es) | 2010-03-10 |
| CN101827819A (zh) | 2010-09-08 |
| EP2190819B1 (en) | 2016-05-25 |
| BRPI0815020A2 (pt) | 2015-03-10 |
| US20090197905A1 (en) | 2009-08-06 |
| JP5581211B2 (ja) | 2014-08-27 |
| NO20100289L (no) | 2010-03-02 |
| AU2008286979B2 (en) | 2013-03-28 |
| EA020658B1 (ru) | 2014-12-30 |
| US20140107143A1 (en) | 2014-04-17 |
| US20170095469A1 (en) | 2017-04-06 |
| KR20100053627A (ko) | 2010-05-20 |
| WO2009023567A1 (en) | 2009-02-19 |
| AU2008286979A1 (en) | 2009-02-19 |
| IL203459A (en) | 2016-02-29 |
| CA2694497A1 (en) | 2009-02-19 |
| EA201070237A1 (ru) | 2010-10-29 |
| US8263807B2 (en) | 2012-09-11 |
| HK1141295A1 (zh) | 2010-11-05 |
| CA2694497C (en) | 2016-07-12 |
| US8563572B2 (en) | 2013-10-22 |
| KR101519682B1 (ko) | 2015-05-19 |
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